Science. Business. Society.
Vol. 11 (2026), Issue 1, pg(s) 3-6

SCIENCE

DFT study of the metal selectivity in protein phosphatases: structural and biomedicinal implications

  • 1 Institute of Optical Materials and Technologies, Bulgarian Academy of Sciences
  • 2 Institute of Optical Materials and Technologies, Bulgarian Academy of Sciences; University Centre on Tautomeric Research and Education in Science and Technolog), University of Plovdiv, Bulgaria
  • 3 Faculty of Chemistry and Pharmacy, Sofia University “St. Kliment Ohridski”, Bulgaria
  • 4 Max Perutz Labs, Vienna Biocenter Campus (VBC), Vienna, Austria; Medical University of Vienna Center for Medical Biochemistry, Vienna, Austria

Abstract

Metal ions are essential for the structural stability and catalytic activity of numerous metalloproteins involved in cellular regulation and signaling. Protein phosphatases such as PHLPP2 and PPM1A play a key role in phosphorylation-dependent pathways with direct biomedical relevance, including cancer-related signaling mechanisms. Still, the factors governing metal selectivity in their active sites remain insufficiently understood. In the present study, Density Functional Theory (DFT) calculations are employed to investigate the metal preferences of two structurally distinct phosphatases: PHLPP2, characterized by a mononuclear Zn²⁺ binding site, and PPM1A, containing a binuclear Mn²⁺ catalytic center. The calculations are performed at the B3LYP/6-31+G(3d,p) level of theory to assess the thermodynamics of metal substitution in biologically relevant coordination environments. The results indicate pronounced differences in structural protection and solvent accessibility between the two metal-binding sites, with the Zn²⁺ site in PHLPP2 exhibiting high thermodynamic stability and well-pronounced protection against competing divalent metal ions. In contrast, the binuclear Mn²⁺ center in PPM1A demonstrates greater flexibility and increased susceptibility to metal exchange, particularly in the presence of biologically abundant cations. Overall, the study demonstrates the applicability of DFT calculations as a predictive tool for investigating metal selectivity in metalloproteins and provides further insight into the possible prospects of innovative cancer-treatment strategies in biologically relevant systems.

Keywords

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